Introduction and Objective: Mice overexpressing a zinc-binding-deficient CRY1 mutant (CRY1C414A; TG) develop a form of diabetes resembling MODY, characterized by β-cell loss associated with features of a cellular senescence. In TG islets, the α/β-cell ratio is increased, and intra-islet duct cells (IIDCs) increase with age. Notably, α-cell neogenesis and clusters of endocrine cells including α cells are observed within and adjacent to IIDC regions. To explore metabolic mechanisms potentially underlying α-cell hyperplasia in TG, we analyzed hepatic metabolic alterations and hormonal profiles. Methods: Liver tissues were collected from TG and wild-type mice (9-16 months old), and the expression of metabolism-related genes was analyzed by quantitative PCR. Plasma samples were subjected to biochemical analysis using dry chemistry assays. Plasma insulin and glucagon levels were measured by ELISA and sandwich ELISA, respectively. Results: Compared with wild-type controls, TG exhibited increased hepatic expression of G6Pase and Pgc-1α, together with upregulation of urea cycle-related genes (Ass1, Asl) and the methionine metabolism-related gene Ahcy. Biochemical analyses revealed significant increases in blood urea nitrogen (BUN) and non-esterified fatty acids (NEFA), suggesting enhanced hepatic utilization of amino acids and fatty acids. Plasma insulin levels were markedly reduced in TG, while plasma glucagon levels showed a nonsignificant trend toward elevation (Student’s t-test). Conclusion: These findings are consistent with increased hepatic amino acid metabolic flux and activation of the liver-α-cell axis in TG. Hepatic metabolic reprogramming combined with reduced insulin levels and relative glucagon predominance may contribute to α-cell hyperplasia in islets. Furthermore, a glucagon-dominant metabolic environment may facilitate α-cell neogenesis and expansion in IIDC regions, suggesting that altered hepatic metabolism plays a key role in shaping islet cell composition in this CRY1 mutant mouse model. Disclosure S. Okano: None. Y. Sasaki: None. A. Yasui: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None. Funding Grants-in-Aid for Scientific Research (24K11670); Tohoku University Institute of Development, Aging and Cancer

Introduction and Objective: We previously demonstrated that KCl-induced depolarization leads to transcriptional changes suggestive of both dedifferentiation and circadian disruption in MIN6 cells. However, the onset, reversibility, and distinction from metabolically driven dedifferentiation remain unclear. It also remains to be determined whether ISX9, a compound suggested to counteract metabolic stress-induced dedifferentiation, affects depolarization-triggered changes. This study aimed to define the early transcriptional dynamics and reversibility of KCl-induced dedifferentiation, alongside associated alterations in circadian gene expression. Methods: MIN6 cells were treated with 40 mM KCl for 3, 6, or 24 hours, with or without 10 μM ISX9. After KCl removal, cells were cultured for an additional 50 hours. Gene expression was analyzed by qPCR for disallowed genes (Aldh1a3, Hk1, Mct1), the β-cell marker Glut2, circadian repressors (Per1, Cry1, Dec1, Chrono, E4bp4), and activator Dbp. Results: Dedifferentiation-associated changes—including upregulation of disallowed genes and Glut2 suppression—were already evident after 3 hours of KCl treatment. After 50 hours of recovery, gene expression shifted toward reversal of these changes, suggesting underlying transcriptional plasticity. Circadian repressors were elevated following KCl-induced depolarization and declined during the recovery phase, indicating dynamic regulation. Dbp expression, which tended to be suppressed by KCl treatment, showed signs of restoration during the recovery phase. ISX9 did not attenuate these effects and was associated with poorer recovery, particularly for disallowed genes. Conclusion: Depolarization rapidly induces transcriptional changes characteristic of β-cell dedifferentiation and circadian disruption, which are partially reversible. ISX9 failed to improve recovery, suggesting mechanistic differences from metabolic stress-induced dedifferentiation. Disclosure S. Okano: None. Y. Sasaki: None. A. Yasui: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None. Funding Grants-in-Aid for Scientific Research (24K11670); Tohoku University Institute of Development, Aging and Cancer

Introduction and Objective: C414A-CRY1 transgenic mice (TG) develop diabetes due to SASP-like phenotypes in β-cells. We demonstrated that mucinous intra-islet ductal cells (IIDCs) expressing TFF2, that is known as a marker of spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach, emerge age-dependently in TG. Reportedly, acinar to ductal metaplasia (ADM) occurs through a process similar to SPEM. To explore the characters of IIDCs and their origins, in this study we examined the expression of SPEM/ADM markers in both β-cells and IIDCs in TG. Methods: By immunostaining the degrees of the expression of IIDCs were judged as strong or negative/weak-positive for SPEM/ADM markers (GKN3, AGR2, AQP5 and GSII-lectin). Markers for Tuft cells (DCLK1, acetylated α-tubulin and TRPM5) were also examined. The positional relationship between GKN3-expressing β-cells and IIDCs was examined. Results: IIDCs reacted to GSII-lectin. GKN3 and AGR2 were expressed in IIDCs. AQP5-positive cells were barely observed in IIDCs. GKN3-expressing partially degranulated β-cells appeared in the regions of adjacent to IIDCs. GKN3 expressing atypical β-cells were located as a constituent of the epithelium of IIDCs as well. Regarding Tuft cell markers, both DCLK1 and acetylated α-tubulin double-positive cells located in IIDCs. TRPM5-expressing cells were also observed in IIDCs. These results indicate that Tuft cells are constituent elements of IIDCs. Conclusion: Our results suggest that IIDCs arise through mechanisms partially common to SPEM/ADM under SASP-like microenvironment in islets. The results indicating the emergence of Tuft cells in the IIDCs reinforce the notion. The GKN3-expressing β-cells might be transitional cells undertaking transdifferentiation toward IIDCs, indicating a possibility that IIDCs could be originated from β-cells. S. Okano: None. A. Yasui: None. S. Kanno: None. Y. Sasaki: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None. Grants-in-Aid for Scientific Research (24K11670); Tohoku University Institute of Development, Aging and Cancer

Regulators of G protein signaling (RGSs) are key modulators of β-cell function and stress adaptation. Similarly, circadian clock components are intricately implicated in the regulation of insulin secretion and β-cell physiology. However, their responses to sustained cellular stimulation under depolarizing conditions remain incompletely understood. MIN6 cells were subjected to prolonged potassium chloride (KCl) exposure to induce sustained membrane depolarization, mimicking conditions of chronic β-cell stimulation. The expression levels of RGSs and core clock genes were analyzed, and associated changes in cellular stress and differentiation markers were assessed.KCl treatment led to the upregulation of endoplasmic reticulum (ER) stress markers, including C/-EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4), with no induction of oxidative stress. Expression of RGS2, RGS4, and RGS16 was elevated. RGS2 partially co-localized with eukaryotic initiation factor-2α (eIF2α), suggesting a role in translational control during stress. Furthermore, KCl-induced depolarization was associated with characteristic changes in β-cell differentiation markers and disallowed genes, indicative of a dedifferentiation-like state. Transcript levels of several circadian genes were altered, including significant downregulation of D-site binding protein (DBP) and upregulation of its repressor E4-binding Protein 4 (E4BP4). Notably, differentiated embryo-chondrocyte expressed gene-1 (DEC1), a clock gene known to be inducible by various external stimuli, was also upregulated, suggesting broader circadian disruption under depolarizing conditions.Sustained membrane depolarization induces ER stress and transcriptional remodeling in MIN6 β-cells, including the modulation of RGS proteins and key circadian regulators such as DBP, E4BP4, and DEC1. These alterations may contribute to functional impairment and a dedifferentiation-like state of β-cells under chronic stimulatory conditions.

Heme serves as a prosthetic group in hemoproteins, including subunits of the mammalian mitochondrial electron transfer chain. The first enzyme in vertebrate heme biosynthesis, 5-aminolevulinic acid synthase 1 (ALAS1), is ubiquitously expressed and essential for producing 5-aminolevulinic acid (ALA). We previously showed that Alas1 heterozygous mice at 20-35 weeks (aged-A1+/-s) manifested impaired glucose metabolism, mitochondrial malformation in skeletal muscle, and reduced exercise tolerance, potentially linked to autophagy dysfunction. In this study, we investigated autophagy in A1+/-s and a sarcopenic phenotype in A1+/-s at 75-95 weeks (senile-A1+/-s). Senile-A1+/-s exhibited significantly reduced body and gastrocnemius muscle weight, and muscle strength, indicating an accelerated sarcopenic phenotype. Decreases in total LC3 and LC3-II protein and Map1lc3a mRNA levels were observed in aged-A1+/-s under fasting conditions and in Alas1 knockdown myocyte-differentiated C2C12 cells (A1KD-C2C12s) cultured in high- or low-glucose medium. ALA treatment largely reversed these declines. Reduced AMP-activated protein kinase (AMPK) signaling was associated with decreased autophagy in aged-A1+/-s and A1KD-C2C12s. AMPK modulation using AICAR (activator) and dorsomorphin (inhibitor) affected LC3 protein levels in an AMPK-dependent manner. Our findings suggest that heme deficiency contributes to accelerated sarcopenia-like defects and reduced autophagy in skeletal muscle, primarily due to decreased AMPK signaling.

Introduction & Objective: We previously suggested that the regions of intra-islet ductal cells (IIDCs) play roles as the source for endocrine cells, particularly for α-cells, in C414A-CRY1 transgenic mice (TG) (ADA 2023), the characters of IIDCs relevant to the α-cell neogenesis are yet unknown. To clarify the points, we conducted experiments in terms of reactivity to DBA-lectin as well as of the expression of TFF2. Methods: The cells constituting developed IIDC (of duct periphery longer than 500 µm) in TG were classified as strongly or weakly positive both for anti-TFF2 antibodies and for DBA-lectin. The positional correlation among glucagon-producing cells present in IIDC compartments and the classified IIDC were examined. Results: Immature IIDCs embedded inside islets were homogeneous for DBA-lectin-reactivity as reported previously: DBA-lectin-weakly positive (ADA 2019). By contrast, it was newly uncovered that developed IIDCs showed variations in phenotypes for the reactivities to DBA-lectin. Heterogeneity in TFF2 expression was also observed in developed IIDCs. Glucagon-producing cells were more frequently located near DBA-lectin-weakly positive IIDCs (~54% higher than near DBA-lectin-strongly positive ones; P<0.01, t-test). While glucagon-producing cells were more frequently located near TFF2-strongly expressing IIDCs (~42% higher than near TFF2-weakly expressing ones; P<0.001, t-test). Furthermore, DBA-lectin-strongly positive IIDCs tended to be TFF2-weakly expressing ones. Conclusion: Our results suggest that TFF2 in IIDCs promotes α-cell neogenesis and/or plays some important roles in the maintenance of newborn α-cells. DBA-lectin-strongly positive characteristics of IIDCs possibly suppress TFF2 expression, thereby acting inhibitory manner for α-cell neogenesis in such IIDCs. S. Okano: None. S. Kanno: None. Y. Sasaki: None. M. Igarashi: None. O. Nakajima: None. Grants-in-Aid for Scientific Research (19K07498); Tohoku University Institute of Development, Aging and Cancer.

C414A-CRY1 transgenic mice (TG) show the symptoms of diabetes due to cellular senescence-like phenotypes in their β-cells as we have reported at ADA Scientific Sessions in 2015. Due to the cellular phenotypes, structural remodeling in islets of TG progresses with age (S. Okano et al., ADA 2016-2022): the increase of the population ratios of α-cell to β-cell and of δ-cell to β-cell as well as the occurrence of fibrillation, angiogenesis and also the generation of mucin-producing intra-islet ductal cells (IIDCs) were observed. Contrary to normal ductal cells, IIDCs only weakly react with DBA lectin, indicating unique characters different from normal ductal cells (ADA 2019). Also, we have shown the results suggesting that δ-cells may play some role as the source for β-cells to supply new β-cells in TG (ADA 2022). To examine the possible roles of IIDCs to maintain of the amount of pancreatic endocrine cells under hyperglycemia for prolonged period in TG, in this study, we conducted detailed immune-staining experiments which focused on fully developed IIDCs, not small ones that still not fully developed. We distinguished IIDCs from normal ducts, PanINs as well as PDGs as the measure of the reactivity to DBA-lectin. Chromogranin A-positive cells were observed in IIDCs, but not in normal ducts, PanINs and PDGs. Then we examined IIDCs with anti-hormone antibodies. In the region of developed IIDCs, cytokeratin 17/19 and glucagon double-positive cells were predominantly observed. Only small portion of somatostatin-positive cells were clearly located adjacent to IIDCs. Cluster of β-cells were located apart from IIDCs. In addition, scrutinized observations suggested the delamination of glucagon-positive cells from the ductal epithelium of the IIDCs. Taken together, these results strongly suggest the possible neogenesis of endocrine cells in IIDCs, that is, IIDCs and their lining cells play roles as the source for endocrine cells, particularly for α, and also for δ cells. Disclosure S. Okano: None. A. Yasui: None. S. Kanno: None. Y. Sasaki: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None. Funding Grants-in-Aid for Scientific Research (19K07498); Tohoku University Institute of Development, Aging and Cancer

Abstract Regulator of G protein signaling proteins (RGSs) are involved in regulating β-cell functions. This study was conducted to examine the cellular responses to the occurrence of β-cell dedifferentiation in terms of the changes of expression levels of Rgs and clock genes: We used MIN6 cells, for which the cellular contents of zinc were reduced by prolonged treatment of the cells by potassium chloride, in this way inducing the cells to a progenitor-like state. The results indicate that endoplasmic reticulum (ER)-stress markers were up-regulated in the treated cells. All examined RGS were up-regulated in treated cells compared with control cells. RGS2 partly co-localized eIF2 α in the treated cells, although no discernable co-localization was observed for RGS4 and 16, suggesting that RGS2 specifically participates in the translational control of protein in response to cellular stresses. Altered mRNA levels of a uniquely specific set of clock genes were observed, suggesting malfunction of the molecular clock in β-cells. Taken together, G protein signaling and translation process are probably fine-tuned by RGSs. Thereby β-cells can cope with stress attributable to the decrease of zinc. The attenuation of circadian rhythm, in addition to some G protein signaling, can be prerequisites for induction of β-cell dedifferentiation.

Cysteine414 (zinc-binding site of mCRY1) -alanine mutant mCRY1 transgenic mice (TG) show diabetes characterized by the reduction of β-cell proliferation due to the characters of senescence-associated secretory phenotype (SASP) in β-cells as we have reported at ADA Scientific Sessions in 2015. We also showed that various structural remodeling progresses in the islets of TG age-dependently: the increase of the population ratios of α-cell to β-cell and of ∂-cell to β-cell as well as fibrillation, angiogenesis and also the generation of mucin-producing atypical intra-islet ducts. Also, we revealed that trefoil factor family 2 (TFF2) is up-regulated in the β-cell of aged TG (Okano S. et al., ADA Scientific Sessions in 2020). To explore the mechanisms of keeping of the amount of β-cells under hyperglycemia for prolonged period in TG, we further conducted detailed double immune-staining experiments in the pancreatic sections of various ages (approximately 1, 10, and 19 months) of TG. The results demonstrated that, somatostatin and insulin double-positive cells were observed exclusively in aged TG (19 months of age). In wild-type mice (WT) of all stages, the double-positive cells were not observed. No glucagon and insulin double-positive cell was observed in islets of both TG and WT of all stages. In addition, scrutinized analyses demonstrated that not only β-cells but also small portion of somatostatin-positive cells express TFF2 in islets of aged TG. Taken together, these results suggest the possible ∂-cell to β-cell transdifferentiation in aged TG, that is, ∂-cells may play some role as the source for β-cells to supply new β-cells for islets in TG. Disclosure S.Okano: None. A.Yasui: None. K.Satoh: None. S.Kanno: None. M.Igarashi: None. O.Nakajima: None. Funding Grants-in-Aid for Scientific Research (19K07498). The Joint Research Program of IDAC, Tohoku University (38).

5-Aminolevulinic acid (ALA) is the rate-limiting intermediate in heme biosynthesis in vertebrate species; a reaction catalyzed by the mitochondrial ALA synthase 1 (ALAS1) enzyme. Previously we reported that knockdown of the ubiquitously expressed ALAS1 gene in mice disrupts normal glucose metabolism, attenuates mitochondrial function and results in a prediabetic like phenotype when animals pass 20-weeks of age (Saitoh et al., 2018). Contrary to our expectations, the cytosolic and mitochondrial heme content of ALAS1 heterozygous (A1+/-) mice were similar to WT animals. Therefore, we speculated that regulatory "free heme" may be reduced in an age dependent manner in A1+/- mice, but not total heme. Here, we examine free and total heme from the skeletal muscle and liver of WT and A1+/- mice using a modified acetone extraction method and examine the effects of aging on free heme by comparing the amounts at 8-12 weeks and 30-36 weeks of age, in addition to the mRNA abundance of ALAS1. We found an age-dependent reduction in free heme in the skeletal muscle and liver of AI+/- mice, while WT mice showed only a slight decrease in the liver. Total heme levels showed no significant difference between young and aged WT and A1+/mice. ALAS1 mRNA levels showed an age-dependent reduction similar to that of free heme levels, indicating that ALAS1 mRNA expression levels are a major determinant for free heme levels. The free heme pools in skeletal muscle tissue were almost 2-fold larger than that of liver tissue, suggesting that the heme pool varies across different tissue types. The expression of heme oxygenise 1 (HO-1) mRNA, which is expressed proportionally to the amount of free heme, were similar to those of free heme levels. Taken together, this study demonstrates that the free heme pool differs across tissues, and that an age-dependent reduction in free heme levels is accelerated in mice heterozygous for ALAS1, which could account for the prediabetic phenotype and mitochondrial abnormality observed in these animals.

Our preceding studies demonstrated that cysteine414 (zinc-binding site of mCRY1) - alanine mutant mCRY1 transgenic mice (TG mice) exhibit diabetes characterized by the reduction of β-cell proliferation caused by senescence-associated secretory phenotype (SASP)-like characters of β-cells. Not only pancreatic intraepithelial neoplasias (PanINs) with pancreatic duct glands (PDGs) but also intra-islet ducts emerged age-dependently in TG mice (Okano S. et al., 2019). Reportedly GRP78 (also called BiP) is highly expressed in pancreatic ductal adenocarcinoma (PDAC), and in lesions of acinar-to-ductal metaplasia (ADM) which is known as precursors of PanIN. As for the islet, GRP78 has been intensively studied with regard to the unfolded protein response (UPR) in the β cells. However, the details of in vivo distribution of GRP78, particularly in endocrine cells outside β cells, are still remain elusive. In this study, we conducted staining experiments for GRP78 in the pancreatic sections of well-matured mice to explore the relation between endocrine cells and intra-islet ducts. The results showed that the expression of GRP78 was higher in PanINs and PDGs than in normal ductal cells in TG mice, suggesting that GRP78 plays important roles in the maintenance of the atypical ductal lesions. In both wild-type and TG mice, GRP78 was observed in the whole islet. The expression of GRP78 was higher in β cells than in alpha and delta cells in both mice. Also, GRP78 was highly expressed in primary intra-islet ducts. Some of the GRP78 high-expressing primary intra-islet ductal cells were co-expressed with chromogranin A, which is known as an endocrine marker. Taken together, our results suggest that the direct trans-differentiation of endocrine cells (possibly β cells) to ductal cells is involved in the generation of the intra-islet ductal cells. Disclosure S. Okano: None. A. Yasui: None. S. Kanno: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None. Funding Japan Society for the Promotion of Science (19K07498); Tohoku University

We have demonstrated that cysteine414 (zinc-binding site of mCRY1)-alanine mutant mCRY1 transgenic mice (Tg mice) show diabetes characterized by the reduction of β-cell proliferation and by β-cell dysfunction due to SASP (senescence-associated secretory phenotype)-like characters of β-cells. In addition, our previous studies showed that mucinous pancreatic duct glands (PDGs) occur in exocrine areas of aged Tg mice. Further, we also showed that mucin-producing intra-islet ducts develope age-dependently in Tg mice (Okano S. et al., 2019). To explore the molecular mechanisms for developing the intra-islet ducts, we conducted DNA microarray analysis using RNA from islets of aged Tg mice. The islet samples were obtained by paraffin-embedded pancreas sections by laser-capture microdissection. The result showed that the mRNA expression of Trefoil factor family 2 (TFF2), which is reportedly expressed in PDGs, was up-regulated in the islet of aged Tg mice. Immunostaining experiments with TFF2 antibodies revealed that, inside of islet of aged Tg mice, TFF2 was expressed by considerable rate in β-cells. TFF2 was located in speckle-like granules in the cytoplasm in the β-cells. In wild type controls, no TFF2 was observed in β-cells. These results suggest that the atypical β-cells have both endocrine and ductal characteristics. In α-cells, essentially no TFF2 protein expression was observed in both wild type controls and Tg mice. Taken together, our results strongly suggest that β-cells are major sources for intra-islet ductal cells in Tg mice. Our results also suggest that direct trans-differentiation of β-cells to ductal cells is involved in the generation of the intra-islet ductal cells. Disclosure S. Okano: None. A. Yasui: None. S. Kanno: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None. Funding Japan Society for the Promotion of Science (19K07498); IDAC; Tohoku University

Our earlier studies demonstrated that cysteine414- (zinc-binding site of mCRY1-) alanine mutant mCRY1 transgenic mice (Tg mice) exhibit diabetes characterized by the reduction of β-cell proliferation and by β-cell dysfunction, presumably caused by senescence-associated secretory phenotype- (SASP-) like characters of islets. Earlier studies also showed that atypical duct-like structures in the pancreas developed age-dependently in Tg mice. Numerous reports have described that karyopherin alpha 2 (KPNA2) is highly expressed in cancers of different kinds. However, details of the expression of KPNA2 in pancreatic ductal atypia and in normal pancreatic tissues remain unclear. To assess the feature of the expression of KPNA2 in the development of the ductal atypia and islet architectures, we scrutinized the pancreas of Tg mice histopathologically. Results showed that considerable expression of KPNA2 was observed in pancreatic β-cells, suggesting its importance in maintaining the functions of β-cells. In mature stages, the level of KPNA2 expression was lower in islets of Tg mice than in wild-type controls. At 4 weeks, the expression levels of KPNA2 in islets of Tg mice were the same as those in wild-type controls. These results suggest that the reduction of KPNA2 might contribute to β-cell dysfunction in mature Tg mice. Additionally, the formation of mucin-producing intra-islet ducts, islet fibrosis, and massive T cell recruitment to the islet occurred in aged Tg mice. In exocrine areas, primary pancreatic intraepithelial neoplasias (PanINs) with mucinous pancreatic duct glands (PDGs) emerged in aged Tg mice. High expression of KPNA2 was observed in the ductal atypia. By contrast, KPNA2 expression in normal ducts was quite low. Thus, upregulation of KPNA2 seemed to be correlated with progression of the degree of atypia in pancreatic ductal cells. The SASP-like microenvironment inside islets might play stimulatory roles in the formation of ductal metaplasia inside islets and in islet fibrosis in Tg mice.

The transgenic mice ubiquitously expressing the zinc-binding site-mutant CRY1 (C414A-CRY1) show early onset diabetes mellitus similar to human MODY characterized by β-cell dysfunction. In the Tg mice with age, atypical ductal structures emerged inside islets, suggesting that islet cells can transdifferentiate to duct-like cells as we have reported at ADA Scientific Sessions in 2017 and 2018. To explore further molecular features of intra-islets ducts, we conducted staining experiments for Dolichos biflorus agglutinin (DBA) lectin in the pancreatic sections of well-matured mice. The results showed that high levels of staining for DBA lectin were observed in normal ducts of both wild type and Tg mice. In contrast, majority of intra-islet ductal structures especially still not fully developed small ones were weakly positive for DBA lectin, suggesting immaturity for ductal functions of the intra-islet ductal cells. Furthermore, the variation of the staining levels for DBA lectin in intra-islet ductal cells was evidently larger than that in other ductal cells, indicating heterogeneity in the cell functions among intra-islet ductal cells. We also found that remarkably high accumulation of FAM98A, an RNA-binding protein whose functions are still not decisive, was observed in the intra-islet ducts in the Tg mice. In normal ducts, moderate staining of FAM98A was observed. As for pancreatic endocrine cells, although as a whole the immunostaining levels were much weaker than those of acini and ductal cells, discernable staining of FAM98A is detected in both α and β cells of islets. Taken together, our results indicate that intra-islet ductal cells have unique feature distinct from normal ductal cells, and suggest that FAM98A may play important roles in the generation of atypical ductal cells from non-ductal cells in the islet. Disclosure S. Okano: None. A. Yasui: None. S. Kanno: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None. Funding Japan Society for the Promotion of Science; Tohoku University